Wright Gerard D
Antimicrobial Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
Adv Drug Deliv Rev. 2005 Jul 29;57(10):1451-70. doi: 10.1016/j.addr.2005.04.002.
Antibiotic resistance can occur via three general mechanisms: prevention of interaction of the drug with target, efflux of the antibiotic from the cell, and direct destruction or modification of the compound. This review discusses the latter mechanisms focusing on the chemical strategy of antibiotic inactivation; these include hydrolysis, group transfer, and redox mechanisms. While hydrolysis is especially important clinically, particularly as applied to beta-lactam antibiotics, the group transfer approaches are the most diverse and include the modification by acyltransfer, phosphorylation, glycosylation, nucleotidylation, ribosylation, and thiol transfer. A unique feature of enzymes that physically modify antibiotics is that these mechanisms alone actively reduce the concentration of drugs in the local environment; therefore, they present a unique challenge to researchers and clinicians considering new approaches to anti-infective therapy. This review will present the current status of knowledge of these aspects of antibiotic resistance and discuss how a thorough understanding of resistance enzyme molecular mechanism, three-dimensional structure, and evolution can be leveraged in combating resistance.
阻止药物与靶点相互作用、抗生素从细胞中外排，以及化合物的直接破坏或修饰。本综述讨论后一种机制，重点关注抗生素失活的化学策略；这些策略包括水解、基团转移和氧化还原机制。虽然水解在临床上尤为重要，特别是应用于β-内酰胺类抗生素时，但基团转移方法最为多样，包括通过酰基转移、磷酸化、糖基化、核苷酸化、核糖基化和硫醇转移进行修饰。对抗生素进行物理修饰的酶的一个独特特征是，这些机制单独就会积极降低局部环境中药物的浓度；因此，对于考虑抗感染治疗新方法的研究人员和临床医生来说，它们带来了独特的挑战。本综述将介绍抗生素耐药性这些方面的当前知识状况，并讨论如何利用对耐药酶分子机制、三维结构和进化的透彻理解来对抗耐药性。
